Uveitis is a group of inflammatory eye diseases that is a major cause of visual loss in the working age group. It is currently estimated that each year in the United States, out of every 100,000 persons, from 17 to 52 will develop uveitis, for a total of over 38,000 new patients per year. It is further estimated that 10% to 15% of the blindness in the United States is due to uveitis. Many uveitis patients have detectable immunological responses to retinal antigens, typically to arrestin (S-antigen) and IRBP, suggesting an autoimmune process in disease pathogenesis. These diseases are genetically controlled by specific human leukocyte antigen (HLA) loci. Vogt-Koyanagi-Haradadisease, sympathetic ophthalmia, and birdshot retinochoroidopathy are major conditions that demonstrate a significant genetic HLA association with both HLA class II and class I molecules. Current treatments of autoimmune uveitis have not always been effective in preventing autoimmune uveitis, particularly recurrent uveitis. This project is a continuation of collaborative work between OHSU and Virogenomics, a biotechnology company that holds an exclusive license (US Patent #6,270,772) for Recombinant T-cell Receptor Ligands (RTLs) therapeutic technology. This new technology is a novel molecule consisting of the a1b1 domains of HLA as a single chain that is covalently linked to an antigenic peptide. RTL drugs are designed to turn off attacking immune cells by altering the function of the subpopulation of T cells that promotes intraocular inflammatory responses. During Phase I studies, we showed that RTLs carrying uveitogenic peptides provided full protection against inflammation in anterior and posterior experimental autoimmune uveitis (EAU) induced in Lewis rats, and that RTLs also prevented recurrent uveitis. In Phase II we propose to evaluate human DR3-derived RTL drugs, using the "humanized"EAU model to determine the efficacy of RTL drugs in preventing uveitis, which will serve as groundwork for Phase I clinical trials in humans. HLA-DR3 mice are susceptible to arrestin- and IRBP-induced uveitis. In this proposed Phase II, we will complete the development of recombinant human DR3- derived RTLs containing arrestin and IRBP uveitogenic peptides and will determine dosage requirements for the therapeutic treatment of EAU in HLA-DR3 Tg mice. We propose the following specific aims: (1)To generate human HLA (2111)-derived RTLs bearing arrestin and IRBP peptides for use in therapeutic treatment of EAU in HLA-DR3 humanized mice;(2) To determine the efficacy of RTLs in suppressing arrestin- and IRBP-induced EAU in HLA-DR3 Tg mice;(3) To determine the specificity of a single RTL in therapy against multiple autoantigens in HLA-DR3 Tg mice. PUBLIC HEALTH RELEVANCE: Uveitis is one of the leading causes of blindness, affecting individuals of all ages, genders, and races. Current treatments of non-infectious autoimmune uveitis have not always been effective in preventing autoimmune uveitis, particularly recurrent uveitis. Recombinant T-cell Receptor Ligands (RTLs) therapeutic technology is new in treatment of autoimmune uveitis. Our Phase I studies showed that RTLs were powerful drugs in protection from MBP-induce anterior uveitis and from IRBP-induced acute and recurrent posterior uveitis, respectively, in Lewis rats without apparent side effects. Overall goal of this project is to develop new human DR3-derived RTLs and determine their efficacy and dosage requirements for the therapeutic treatment of patients with autoimmune uveitis.